This invention relates to a process for production of amides by reaction of an ester with an amine in the presence of a substance which promotes this reaction. The reaction is generally described by the following formula ##STR1## in which R is .alpha.-halo-C.sub.1 -C.sub.8 -alkyl; R.sub.1 is C.sub.1 -C.sub.8 alkyl; and R.sub.2 and R.sub.3 are C.sub.1 -C.sub.8 alkyl, and may be the same or different alkyl groups.
The term "alkyl" includes both straight and branched chain groups of this type. The term ".alpha.-halo-C.sub.1 -C.sub.8 alkyl" includes both straight and branched chain alkyl groups having a halogen atom (chlorine, fluorine, or bromine, preferably chlorine) bonded to the carbon atom adjacent (.alpha.) to the carboxyl moiety. The alkyl portion of this haloalkyl moiety may optionally be substituted by additional halogen atoms, bonded to other carbon atoms.
In a preferred embodiment, the products of the process of this invention are optically active amides; in the most preferred embodiment the .alpha.-carbon atom (to which the halogen is bonded) is optically active. In further preferred embodiments, R is .alpha.-halo-C.sub.1 -C.sub.4 -alkyl, R.sub.1 is C.sub.1 -C.sub.4 -alkyl, R.sub.2 is C.sub.2 -C.sub.4 alkyl and R.sub.3 is C.sub.1 -C.sub.4 alkyl.
The substances which have been found suitable for promoting this reaction are selected from the group consisting of halides of metals in Group IIIa having a molecular weight of 26 or greater, and of metals in Group IVb. Of the Group IIIa metal halides, those of aluminum, particularly aluminum trichloride and aluminum tribromide, are preferred. Of those of Group IVb, halides of titanium and zirconium, particularly the tetrachlorides, and most preferably zirconium tetrachloride, are preferred.
In its most preferred form, the present process provides a method for the preparation of optically active amides of lower .alpha.-haloalkyl carboxylic acids. Most preferably, the process relates to the production of L-N,N-diethyl-2-halopropionamides, and particularly to the chloropropionamides of this type, by a one-step preparation from the corresponding L-(lower alkyl)-2-halopropionate, preferably from an L-methyl2-halopropionate.
Some methods for the production of such compounds are given in the article by Snatzke, et al., Chem. Ber., 106, pp. 2072-2075 (1973). These include the reaction of optically active lactic acid with thionyl chloride and reaction of alanines with sodium nitrite in the presence of HCl or HBr. The former process produces the desired compound in only about 23% yield; the latter process requires several steps.
The reaction of esters with amines to produce amides is well known in the prior art. One example is the article by Yazawa, Tetrahedron Letters, No. 46, pp. 3995-3996 (1974), which describes the reaction of esters and amines in the presence of boron tribromide to produce amides. Another article of interest is the publication by Chandra, et al., J. Chem. Soc. (C), 1969, pp. 2565-2568, which describes the reaction of carbonyl compounds, including carboxylic acids, anhydrides, and esters, with a metal amide, particularly a titanium amide. Alternatively, it is suggested to use a complex formed by reaction of titanium tetrachloride with a secondary amine. Such a process requires either the production or purchase of the metal amide, which is rather expensive, and also requires at least two steps.
U.S. Pat. No. 3,655,690 relates to the production of certain amides by reaction of a carboxylic acid or salt thereof with an amine. Certain metal halides are said to be useful as catalysts for the reaction. U.S. Pat. No. 3,763,234 describes a process for production of amides by reaction of esters and amines in the presence of Lewis acids, preferably uranium salts, as catalysts. In this process, the Lewis acid is used in at least 0.005 mole %. Reaction times are said to vary from 0.1 to 48 hours. The statement is made that use of the Lewis acid in amounts greater than 25 mole % provides "no particular advantage."